Pyrazolopyridine compound and pharmaceutical use thereof

ABSTRACT

A pyrazolopyridine compound of formula (I) wherein R 1  is aryl, and R 2  is lower alkyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have one or more substituent(s); a group of formula (1) wherein R 3  is hydrogen, lower alkyl, ar(lower)alkyl or acyl, R 4  is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is an integer of 1 or 2; a group of formula (2) wherein R 5  and R 6  are each lower alkyl; or quinuclidinyl, or a salt the The pyrazolopyridine compound (I) and a salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer&#39;s disease, cerebrovascular dementia, Parkinson&#39;s disease, etc.), anxiety, pain, cerebrovascular disease (e.g. stroke, etc.), heart failure, and the like.

This Application is a 371 of PCT/JP97/02493 filed Jul. 17, 1997.

FIELD OF THE INVENTION

The present invention relates to a novel pyrazolopyridine compound and asalt thereof which are useful as medicaments.

BACKGROUND ART

Some pyrazolopyridine compounds to be useful as psychostimulant, remedyfor renal failure, or the like are known (e.g. EP-0299209, EP-0379979,etc.).

DISCLOSURE OF THE INVENTION

The present invention relates to a novel pyrazolopyridine compound and asalt thereof useful as medicaments; processes for the preparation ofsaid pyrazolopyridine compound and a salt thereof; a pharmaceuticalcomposition comprising, as an active ingredient, said pyrazolopyridinecompound or a pharmaceutically acceptable salt thereof; a use of saidpyrazolopyridine compound or a pharmaceutically acceptable salt thereofas a medicament; and a method for using said pyrazolopyridine compoundor a pharmaceutically acceptable salt thereof for therapeutic purposes,which comprises administering said pyrazolopyridine compound orpharmaceutically acceptable salt thereof to a human being or an animal.

The pyrazolopyridine compound and a salt thereof are adenosineantagonists (especially, A₁ receptor antagonist) and possess variouspharmacological actions such as cognitive enhancing action, analgesicaction, locomotor action, antidepressant action, diuretic action,cardioprotective effect, cardiotonic action, vasodilating action (e.g.cerebral vasodilating action, etc.), the action of increasing the renalblood flow, renal protective effect, improvement action of renalfunction, enhancing action of lipolysis, inhibition action ofanaphylactic bronchoconstriction, acceleration action of the insulinrelease, the action of increasing the production of erythropoietin,inhibiting action of platelet aggregation, or the like.

They are useful as cognitive enhancer, antidementia drug,psychostimulant, analgesic, cardioprotective agent, antidepressant,ameliorants of cerebral circulation, tranquilizer, drug for heartfailure, cardiotonic agent, anti-hypertensive agent, drug for renalfailure (renal insufficiency), drug for renal toxicity, renal protectiveagent, drug for improvement of renal function, diuretic, drug for edema,anti-obesity, antiasthmatic, bronchodilator, drug for apnea, drug forgout, drug for hyperuricemia, drug for sudden infant death syndrome(SIDS), ameliorants of immunosuppressive action of adenosine,antidiabetic agent, drug for ulcer, drug for pancreatitis, drug forMeniere's syndrome, drug for anemia; drug for thrombosis, drug formyocardial infarction, drug for obstruction, drug for arteriosclerosisobliterans, drug for thrombophlebitis, drug for cerebral infarction,drug for transient ischemic attack, drug for angina pectoris, or thelike; and useful for the prevention and/or treatment of depression,dementia (e.g. Alzheimer's disease, cerebrovascular dementia,Parkinson's disease, etc.), anxiety, pain, cerebrovascular disease (e.g.stroke, etc.), heart failure; hypertension (e.g. essential hypertension,nephrogenous hypertension, etc.); circulatory insufficiency (acutecirculatory insufficiency) caused by, for example, ischemia/reperfusioninjury (e.g. myocardial ischemia/reperfusion injury, cerebralischemia/reperfusion injury, peripheral ischemia/reperfusion injury,etc.), shock (e.g. endotoxin shock, hemorrhagic shock, etc.), surgicalprocedures or the like; post-resuscitation asystole; bradyarrhythmia;electromechanical dissociation; hemodynamic collapse; SIRS (systemicinflammatory response syndrome); multiple organ failure; renal failure(renal insufficiency) (e.g. acute renal failure, etc.), renal toxicity[e.g. renal toxicity induced by a drug such as cisplatins, gentamicin,FR-900506 (disclosed in EP-0184162), cyclosporin (e.g. cyclosporin A) orthe like; glycerol, etc.], nephrosis, nephritis, edema (e.g. cardiacedema, nephrotic edema, hepatic edema, idiopathic edema, drug edema,acute angioneurotic edema, hereditary angioneurotic edema, carcinomatousascites, gestational edema, etc.); obesity, bronchial asthma, gout,hyperuricemia, sudden infant death syndrome, immunosuppression,diabetes, ulcer such as peptic ulcer (e.g. gastric ulcer, duodenalulcer, etc.), pancreatitis, Meniere's syndrome, anemia, dialysis-inducedhypotension, constipation, ischemic bowel disease, ileus (e.g.mechanical ileus, adynamic ileus, etc.); myocardial infarction,thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.),obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebralinfarction, transient ischemic attack, angina pectoris, or the like.

The novel pyrazolopyridine compound of the present invention can beshown by the following formula (I). ##STR1## wherein R¹ is aryl, and

R² is lower alkyl substituted with unsaturated 3 to 8-memberedheteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), which may have one or more substituent(s); a group ofthe formula: ##STR2## [wherein R³ is hydrogen, lower alkyl,ar(lower)alkyl or acyl,

R⁴ is hydrogen or hydroxy,

A is lower alkylene,

m is an integer of 0 or 1, and

n is an integer of 1 or 2];

a group of the formula: ##STR3## [wherein R⁵ and R⁶ are each loweralkyl]; or quinuclidinyl, or a salt thereof.

The object compound (I) and a salt thereof of the present invention canbe prepared by the following reaction schemes. ##STR4## wherein R¹ andR² are each as defined above,

R^(3a) is acyl,

R^(2b) is a group of formula: ##STR5## wherein A, m, n, R^(3a) and R⁴are each as defined above;

R^(2c) is a group of formula: ##STR6## wherein A, m, n and R⁴ are eachas defined above and R^(3b) is hydrogen;

R^(2d) is a group of formula: ##STR7## wherein A, m, n and R⁴ are eachas defined above and R^(3c) is lower alkyl;

R^(2e) is a group of formula: ##STR8## wherein A, m, n, R^(3c) and R⁴are each as defined above, or a group of formula: ##STR9## wherein R⁵and R⁶ are each as defined above; and

X is a leaving group.

In addition to the processes as mentioned above, the object compound (I)and a salt thereof can be prepared, for example, according to theprocedures as illustrated in Examples in the present specification or ina manner similar thereto.

The starting compounds can be prepared, for example, according to theprocedures as illustrated in Preparations in the present specificationor in a manner similar thereto.

The object compound (I) and a salt thereof can be prepared according tothe methods as shown in Preparations or Examples, or in a manner similarthereto.

It is to be noted that the object compound (I) may include thegeometrical isomer(s) due to the double bond(s) and/or the stereoisomer(s) due to the asymmetric carbon atom(s). In this regard, oneisomer can be converted to another according to a conventional method inthis field of the art.

It is also to be noted that the solvating form of the compound (I) (e.g.hydrate, etc.) and any form of the crystal of the compound (I) areincluded within the scope of the present invention.

Suitable salts of the object compound (I) are conventionalpharmaceutically acceptable ones and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), aninorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine,aspartic acid, glutamic acid, etc.), and the like.

Suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof and which appear inthe above and following description in the present specification areexplained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unlessotherwise indicated.

Suitable "lower alkyl" may include straight or branched ones such asmethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl orthe like, in which the preferred one may be (C₁ -C₄) alkyl and the morepreferred one may be methyl.

Suitable "unsaturated 3 to 8-membered heteromonocyclic group containing1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s)", which group may have1 to 3 substituent(s) (e.g. lower alkyl, etc.), may include thiazolyl,isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, and thelike, in which the preferred one may be 5 or 6-membered one, and themore preferred one may be thiazolyl.

Suitable "acyl" may include lower alkanoyl (e.g. formyl, acetyl,propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, etc.); carboxy;protected carboxy; hydroxysulfonyl; and the like.

Suitable "protected carboxy" may be

(1) an esterified carboxy, in which concrete examples may be the onessuch as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,1-cyclopropylethoxycarbonyl, etc.) which may have substituent(s), forexample, lower alkanoyloxy(lower) alkoxycarbonyl [e.g.acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl,butyryloxymethoxycarbonyl, valeryloxy-methoxycarbonyl,pivaloyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl,1-propionyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl,2-propionyloxyethoxycarbonyl, hexanoyloxymethoxycarbonyl, etc.]; loweralkanesulfonyl(lower)alkoxycarbonyl [e.g. 2-mesylethoxycarbonyl, etc.];

mono(or di or tri)halo(lower)alkoxycarbonyl [e.g. 2-iodoethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc.]; lower alkenyloxycarbonyl [e.g.vinyloxycarbonyl, allyloxycarbonyl, etc.];

lower alkynyloxycarbonyl [e.g. ethynyloxycarbonyl, propynyloxycarbonyl,etc.];

ar(lower)alkoxycarbonyl [preferably mono-(or di- ortri-)phenyl(lower)alkoxycarbonyl] which may have substituent(s) [e.g.benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-nitro-benzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl,benzhydryloxycarbonyl, bis(methoxyphenyl)methoxycarbonyl,3,4-dimethoxybenzyloxycarbonyl,4-hydroxy-3,5-di-tert-butylbenzyloxycarbonyl, etc.];

aryloxycarbonyl which may have substituent(s) [e.g. phenoxycarbonyl,4-chlorophenoxycarbonyl, tolyloxycarbonyl, 4-tert-butylphenoxycarbonyl,xylyloxycarbonyl, mesityloxycarbonyl, cumenyloxycarbonyl, etc.] or thelike;

(2) amidated carboxy, in which concrete examples may be carbamoyl;

N-(lower)alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl,N-hexylcarbamoyl, etc.);

N-(higher)alkylcarbamoyl (e.g. N-heptylcarbamoyl,N-(2-methylheptyl)carbamoyl, N-nonylcarbamoyl, N-decanylcarbamoyl,

N-tricyclo[3.3.1.1³.7 decanylcarbamoyl, N-undecanylcarbamoyl,

N-(bicyclo[4.3.2]undecanyl)carbamoyl,

N-dodecanylcarbamoyl, N-tridecanylcarbamoyl,

N-tetradecanylcarbamoyl, N-pentadecanylcarbamoyl,

N-hexadecanylcarbamoyl, N-heptadecanylcarbamoyl,

N-octadecanylcarbamoyl, N-nonadecanylcarbamoyl,

N-icosanylcarbamoyl, etc.);

N,N-di(lower)alkylcarbamoyl [e.g. N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-di(tert-butyl)carbamoyl, N-pentyl-N-hexylcarbamoyl, etc.];

N-lower alkyl-N-ar(lower)alkylcarbamoyl (e.g.N-methyl-N-benzylcarbamoyl, etc.);

N-carboxy(lower)alkylcarbamoyl [e.g. N-carboxymethylcarbamoyl,N-(2-carboxyethyl)carbamoyl, N-(2-carboxypropyl)carbamoyl,N-(3-carboxypropyl)carbamoyl, N-(1-carboxymethylethyl)carbamoyl,N-(4-carboxybutyl)carbamoyl, N-(2-carboxymethyl-2-methylethyl)carbamoyl,N-(5-carboxypentyl)carbamoyl, N-(3-carboxyhexyl) carbamoyl, etc.];

N-protected carboxy(lower)alkylcarbamoyl, in which the preferred one maybe N-esterified carboxy(lower)alkylcarbamoyl, and the more preferred onemay be N-lower alkoxycarbonyl(lower)alkylcarbamoyl [e.g.

N-(methoxycarbonylmethyl)carbamoyl,

N-(ethoxycarbonylmethyl)carbamoyl,

N-(2-ethoxycarbonylethyl)carbamoyl,

N-(2-tert-butoxycarbonylethyl)carbamoyl,

N-(3-methoxycarbonylpropyl)carbamoyl,

N-(1-propoxycarbonylpropyl)carbamoyl,

N-(1-isopropoxycarbonylmethylethyl)carbamoyl,

N-(butoxycarbonylmethyl)carbamoyl,

N-(tert-butoxycarbonylmethyl)carbamoyl,

N-(4-isobutoxycarbonylbutyl)carbamoyl,

N-(2-tert-butoxycarbonylmethyl-2-methylethyl)carbamoyl,

N-(3-pentyloxycarbonylpentyl)carbamoyl,

N-(6-hexyloxycarbonylhexyl)carbamoyl,

N-[(1-cyclopropylethoxy)carbonylmethyl carbamoyl, etc.];

N-lower alkyl-N-carboxy(lower)alkylcarbamoyl [e.g.N-methyl-N-(carboxymethyl)carbamoyl,N-methyl-N-(2-carboxyethyl)carbamoyl,N-ethyl-N-(2-carboxypropyl)carbamoyl,N-propyl-N-(3-carboxypropyl)carbamoyl,N-isopropyl-N-(1-carboxymethylethyl)carbamoyl,N-butyl-N-(4-carboxybutyl)carbamoyl,N-tert-butyl-N-(2-carboxymethyl-2-methylethyl)carbamoyl,N-pentyl-N-(5-carboxypentyl)carbamoyl,N-hexyl-N-(3-carboxyhexyl)carbamoyl, etc.];

N-lower alkyl-N-protected carboxy(lower)alkylcarbamoyl, in which thepreferred one may be N-lower alkyl-N-esterifiedcarboxy(lower)alkylcarbamoyl, and the more preferred one may be N-loweralkyl-N-lower alkoxycarbonyl(lower)alkylcarbamoyl [e.g.N-methyl-N-(methoxycarbonylmethyl)carbamoyl,N-methyl-N-(ethoxycarbonylmethyl)carbamoyl,N-methyl-N-(2-ethoxycarbonylethyl)carbamoyl,N-ethyl-N-(2-tert-butoxycarbonylethyl)carbamoyl,N-propyl-N-(3-methoxycarbonylpropyl)carbamoyl,N-isopropyl-N-(1-propoxycarbonylpropyl)carbamoyl,N-propyl-N-(1-isopropoxycarbonylmethylethyl)carbamoyl,N-butyl-N-(butoxycarbonylmethyl)carbamoyl,N-isobutyl-N-(tert-butoxycarbonylmethyl)carbamoyl,N-butyl-N-(4-isobutoxycarbonylbutyl)carbamoyl,N-methyl-N-(2-tert-butoxycarbonylmethyl-2-methylethyl)carbamoyl,N-pentyl-N-(3-pentyloxycarbonylpentyl)carbamoyl,N-hexyl-N-(6-hexyloxycarbonylhexyl)carbamoyl,N-ethyl-N-[(1-cyclopropylethoxy)carbonylmethyl]carbamoyl, etc.];

N-hydroxy(lower)alkylcarbamoyl [e.g. N-hydroxymethylcarbamoyl,N-(2-hydroxyethyl)carbamoyl, N-(1-hydroxyethyl)carbamoyl,N-(3-hydroxypropyl)carbamoyl, N-(1-hydroxybutyl)carbamoyl,N-(2-hydroxymethyl-2-methylethyl)carbamoyl,N-(5-hydroxypentyl)carbamoyl, N-(3-hydroxyhexyl)carbamoyl, etc.]; agroup of the formula: ##STR10## wherein a group of the formula:##STR11## is N-containing heterocyclic group which may have one or moresubstituent(s), in which N-containing heterocyclic group may containhetero atom(s) such as N, O or S in its ring; or the like; or the like.

Suitable example of the aforesaid "N-containing heterocyclic group" mayinclude saturated or unsaturated, monocyclic or polycyclic heterocyclicgroup such as

unsaturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,azepinyl (e.g. 1H-azepinyl, etc.), pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.) etc.;

saturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,perhydroazepinyl (e.g. perhydro-1H-azepinyl, etc.), pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

saturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, 7-azabicyclo[2.2.1]heptyl,3-azabicyclo[3.2.2]nonanyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, dihydrooxazinyl (e.g.5,6-dihydro-4H-dihydro-1,3-oxazinyl, etc.), oxazolyl, isoxazolyl,oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 or 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.;

unsaturated condensed heterocyclic group containing 1 or 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

in which the preferred one may include saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s),

saturated 3 to 8-membered heteromonocyclic group containing 1 or 2oxygen atom(s) and 1 to 3 nitrogen atom(s); and

saturated 3 to 8-membered heteromonocyclic group containing 1 or 2sulfur atom(s) and 1 to 3 nitrogen atom(s).

The "N-containing heterocyclic group" thus defined may have one or more(preferably 1 to 3) substituent(s) such as lower alkyl as mentionedabove;

hydroxy(lower)alkyl (e.g. hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxybutyl, 1-methyl-1-hydroxymethylethyl,4-hydroxypentyl, 3-hydroxyhexyl, etc.);

lower alkoxy(lower)alkyl (e.g. methoxymethyl, 2-methoxyethyl,1-ethoxyethyl, 3-propoxypropyl, 2-(tert-butoxy)butyl, 5-pentyloxypentyl,3-hexyloxyhexyl, etc.);

acyloxy(lower)alkyl such as lower alkanoyloxy(lower)alkyl (e.g.acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl,3-propionyloxypropyl, 2-butyryloxybutyl, 4-pivaloyloxypentyl,6-hexanoyloxyhexyl, etc.) or the like;

protected carboxy such as lower alkoxycarbonyl as mentioned above;carboxy; ar(lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl,phenethyl, etc.), diphenyl(lower)alkyl (e.g. benzhydryl, etc.) ortriphenyl(lower)alkyl (e.g. trityl, etc.); lower alkylamino (e.g.methylamino, ethylamino, propylamino, butylamino, tert-butylamino,pentylamino, hexylamino, etc.); acyl such as lower alkanoyl as mentionedabove; or the like.

Suitable "aryl" may include phenyl, naphthyl, anthryl, and the like, inwhich the preferred one may be (C₆ -C₁₀) aryl, and the more preferredone may be phenyl.

This "aryl" may have one or more (preferably 1 to 3) substituent(s)selected from the group consisting of halogen (e.g. fluoro, chloro,bromo, iodo), lower alkyl as mentioned above, lower alkoxy (e.g.methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,etc.), hydroxy, lower alkylsilyloxy (e.g. trimethylsilyloxy,tert-butyldimethylsilyloxy, etc.), phenyl(lower)alkoxy (e.g.phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy,phenylpentyloxy, phenylhexyloxy, etc.), phenyl which may havehalo(lower)alkyl (e.g. trifluoromethylphenyl, etc.), and the like.

Suitable "ar(lower)alkyl" may include phenyl(lower)alkyl (e.g. benzyl,phenethyl, etc.), diphenyl(lower)alkyl (e.g. benzhydryl, etc.) ortriphenyl(lower)alkyl (e.g. trityl, etc.) and the like, in which thepreferred one may be phenyl(lower)alkyl, and the more preferred one maybe phenyl (C₁ -C₄) alkyl.

This "ar(lower)alkyl" may have one or more (preferably 1 to 3)substituent(s) such as lower alkoxy as mentioned above, and the like.

Suitable "lower alkylene" may include straight or branched ones such asmethylene, ethylene, trimethylene, propylene, tetramethylene,pentamethylene, hexamethylene, and the like, in which the preferred onemay be (C₁ -C₄) alkylene, and the more preferred ones are methylene andethylene.

Suitable "a leaving group" may include halogen as mentioned above,hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.),sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), and the like.

Of the object pyrazolopyridine compounds (I),

(1) the preferred one may be the compound (I) wherein

R¹ is phenyl, and

R² is lower alkyl substituted with thiazolyl which may have 1 to 3 loweralkyl;

a group of the formula; ##STR12## [wherein R³ is hydrogen, lower alkyl,phenyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, orphenyl(lower)alkoxycarbonyl,

R⁴ is hydrogen or hydroxy,

A is lower alkylene,

m is an integer of 0 or 1, and

n is an integer of 1 or 2];

a group of the formula: ##STR13## [wherein R⁵ and R⁶ are each loweralkyl]; or quinuclidinyl, and

(2) the more preferred one may be the compound (I) wherein

R¹ is phenyl, and

R² is lower alkyl substituted with thiazolyl which may have 1 to 3 loweralkyl, and

(3) the most preferred one may be the compound (I) wherein

R¹ is phenyl, and

R² is a group of the formula: ##STR14## [wherein R³ is hydrogen, loweralkyl, phenyl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl,

R⁴ is hydrogen,

A is lower alkylene,

m is an integer of 0, and

n is an integer of 1 or 2], and

(4) the most particularly preferred one may be the compound (I) wherein

R¹ is phenyl, and

R² is a group of the formula; ##STR15## [wherein R³ is lower alkyl,

R⁴ is hydrogen,

A is lower alkylene,

m is an integer of 0, and

n is an integer of 2].

The processes for the preparation of the object compound (I) and a saltthereof (Process 1 to 7) are explained in detail in the following.

Process 1

The compound (I) and a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (III) or a saltthereof.

Suitable salt of the compound (III) can be referred to the ones asexemplified for the compound (I).

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene,toluene, methylene chloride, ethylene chloride, formamide,N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol,diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, dimethylsulfoxide, or any other organic solvent which does not adversely affectthe reaction, preferably in ones having strong polarities. Among thesolvents, hydrophillic solvents may be used in a mixture with water.When the compound (III) is in liquid, it can also be used as a solvent.

The reaction is preferably conducted in the presence of a base, forexample, inorganic base such as alkali metal hydroxides alkali metalalkoxide, alkali metal carbonate, alkali metal bicarbonate, alkali metalhydride, organic base such as benzyltrimethylammonium hydroxide,trimethylamine, and the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling, at ambient temperature, under warming orunder heating.

The present reaction is preferably carried out in the presence of alkalimetal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metalthiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.),di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate,diisopropyl azodicarboxylate, etc.) or the like.

When X is --OH, activation of OH with triphenylphosphine and the likemay be necessary.

Process 2

The compound (Ia) and a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (IV).

The reaction of this process can be carried out in a manner similar tothat in Process 1.

Process 3

The compound (Ic) and a salt thereof can be prepared by subjecting thecompound (Ib) or a salt thereof to elimination reaction of acyl.

Suitable salts of the compound (Ib) and (Ic) can be referred to the onesas exemplified for the compound (I).

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic baseand an organic base such as an alkali metal (e.g. sodium, potassium,etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), thehydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g.trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]undec-7-ene, or the like.

Suitable acid may include an organic acid (e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.),and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). Theelimination using Lewis acid such as trihaloacetic acid (e.g.trichloroacetic acid, trifluoroacetic acid, etc.) or the like ispreferably carried out in the presence of cation trapping agents (e.g.anisole, phenol, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g. methanol, ethanol, etc.), methylene chloride,tetrahydrofuran, dioxane, a mixture thereof or any other solvent whichdoes not adversely influence the reaction. A liquid base or acid can bealso used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction of this process can be also carried out according to aconventional reduction method employed in this field of the art (e.g.chemical reduction, catalytic reduction, etc.).

Process 4

The compound (Ic) and a salt thereof can be prepared by subjecting thecompound (Id) or a salt thereof to dealkylation reaction.

Suitable salts of the compound (Ic) and (Id) can be referred to the onesas exemplified for the compound (I).

This reaction can be carried out by reacting the compound (Id) or a saltthereof with a dealkylating agent.

The dealkylating agent is halo(lower)alkyl haloformate and the like.

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

Process 5

The compound (Ie) and a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to alkylation reaction.

Suitable salts of the compound (Ic) and (Ie) can be referred to the onesas exemplified for the compound (I).

This reaction can be carried out by reacting the compound (Ic) or a saltthereof with an alkylating agent.

The alkylating agent is lower alkyl halide and the like.

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

The present reaction is preferably carried out in the presence of alkalimetal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metalthiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.) orthe like.

Process 6

The compound (Ib) and a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to acylation reaction.

Suitable salts of the compound (Ib) and (Ic) can be referred to the onesas exemplified for the compound (I).

This reaction can be carried out by reacting the compound (Ic) or a saltthereof with an acylating agent.

The acylating agent is acyl halide corresponding to the acyl to beintroduced, acyl anhydride corresponding to the acyl to be introduced,and the like.

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

Process 7

The compound (If) and a salt thereof can be prepared by subjecting thecompound (V) or a salt thereof to formation reaction of thiazole ring.

Suitable salts of the compound (V) and (If) can be referred to the onesas exemplified for the compound (I).

This reaction can be carried out by reacting the compound (V) or a saltthereof with a haloacetaldehyde or its reactive derivative.

The haloacetaldehyde or its reactive derivative is bromoacetaldehydediethyl acetal, and the like.

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

The object compound (I) of the present invention is an adenosineantagonist and possesses the various pharmacological actions as statedbefore.

In order to show the usefulness of the compound (I) of the presentinvention, the pharmacological test result of the representativecompound of the present invention is shown in the following.

Test: Adenosine Antagonistic Activity

[I] Test Method

The adenosine antagonistic activity of the test compound was examined byradioligand binding techniques using 8-cyclopentyl-1,3-dipropylxanthine,dipropyl-2,3-³ H(N)] (³ H-DPCPX, 2×10⁻⁹ M) for human A¹ receptor.

[II] Test Compound

3-[2-(1-Methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(the compound of Example 2)

[III] Test Result

The inhibition (%) was more than 90% at the dose of 1.0×10⁻⁷ (M).

The pyrazolopyridine compound (I) and a salt thereof of this inventionare usuful as adenosine antagonists and for the prevention and/or thetreatment of depression, dementia (e.g. Alzheimer's disease,cerebrovascular dementia, Parkinson's disease, etc.), anxiety, pain,cerebrovascular disease (e.g. stroke, etc.), heart failure, and thelike.

The pharmaceutical composition of this invention can be used in the formof a pharmaceutical preparation, for example, in a solid, semisolid orliquid form, which contains the pyrazolopyridine compound (I) or apharmaceutically acceptable salt thereof as an active ingredient inadmixture with an organic or inorganic carrier or excipient suitable forrectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external(topical), oral or parenteral (including subcutaneous, intravenous andintramuscular) administrations or insufflation. The active ingredientmay be compounded, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, troches,capsules, suppositories, creams, ointments, aerosols, powders forinsufflation, solutions, emulsions, suspensions, and any other formsuitable for use. In addition, auxiliary, stabilizing agents, thickeningagents, coloring agents and perfumes may be used where necessary. Thepyrazolopyridine compound (I) or a pharmaceutically acceptable saltthereof is included in a pharmaceutical composition in an amountsufficient to produce the desired aforesaid pharmaceutical effect uponthe process or condition of diseases.

For applying the composition to a human being or an animal, it ispreferable to apply it by intravenous, intramuscular, pulmonary or oraladministration, or insufflation. While the dosage of therapeuticallyeffective amount of the pyrazolopyridine compound (I) varies dependingon the age and condition of each individual patient to be treated, inthe case of intravenous administration, a daily dose of 0.01-100 mg ofthe pyrazolopyridine compound (I) per kg weight of a human being or ananimal, in the case of intramuscular administration, a daily dose of0.1-100 mg of the pyrazolopyridine compound (I) per kg weight of a humanbeing or an animal, and in case of oral administration, a daily dose of0.5-100 mg of the pyrazolopyridine compound (I) per kg weight of a humanbeing or an animal is generally given for the prevention and/ortreatment of the aforesaid diseases.

The following Preparation and Examples are given for the purpose ofillustrating the present invention in more detail.

Preparation 1

Into a mixture of3-(2-cyanomethyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(2.0 g) and triethylamine (1.02 ml) in pyridine (10 ml) was introducedhydrogen sulfide at 50° C. for 6 hours. The mixture was poured intowater. The resulting solid was collected by filtration to give3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(2.18 g).

mp: 220.0-221.0° C. (EtOH)

IR (Nujol): 3400, 3270, 3180, 1650, 1610, 1575 cm⁻¹

NMR (DMSO-d₆, δ): 5.03 (2H, s), 6.89 (1H, d, J=9.7 Hz), 7.03-7.08 (1H,m), 7.06 (1H, d, J=9.7 Hz), 7.36-7.50 (4H, m), 7.64-7.70 (2H, m), 8.04(1H, d, J=8.9 Hz), 8.80 (1H, d, J=6.9 Hz), 9.42 (1H, s), 9.86 (1H, s).

(+)-APCI/MS (m/z): 362 (M+H)⁺

Anal. Calcd. for C₁₉ H₁₅ N₅ OS.1/2H₂ O: C 61.61, H 4.35, N 18.91

Found: C 61.54, H 4.25, N 18.85

Preparation 2

To a solution of 4-piperidone hydrochloride (25 g) in a mixture of water(200 ml) and tetrahydrofuran (200 ml) was added dropwise benzylchloroformate (29 ml) at 0 to 10° C., and the pH (pH 8.5-9.5) wasadjusted with addition of 30% aqueous sodium hydroxide.

To the reaction mixture was added ethyl acetate (250 ml) and organicphase was separated, which was washed two times with 200 ml of saturatedsodium chloride in water and dried over magnesium sulfate.

Evaporation of the solvent gave 1-benzyloxycarbonyl-4-piperidone (42.5g, 98.8% yield).

NMR (CDCl₃, δ): 2.45 (4H, t, J=6.2 Hz), 3.79 (4H, t, J=6.3 Hz), 5.18(2H, s), 7.36-7.40 (5H, m).

(+)-APCI/MS: 234 (M⁺ +1).

Preparation 3

To a suspension of sodium hydride (7.92 g, 60% dispersion in mineraloil) in dimethyl sulfoxide (250 ml) was added by portionstrimethylsulfoxonium iodide (41.63 g) at room temperature under nitrogenatmosphere.

After stirring for 1 hour, to the reaction mixture was added dropwise1-benzyloxycarbonyl-4-piperidone (42 g), and the mixture was heated to55° C. and stirred for 4 hours.

The reaction mixture was poured into ice water (800 ml) and extractedthree times with 800 ml of ethyl acetate.

Organic phase was combined, washed with water (500 ml×3) and saturatedsodium chloride in water, and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed onsilica gel eluting with 20% ethyl acetate in n-hexane to give1-benzyloxycarbonylpiperidine-4-spiro-2'-oxirane (23.25 g, 52.2% yield).

NMR (CDCl₃, δ): 1.39-1.51 (2H, m), 1.76-1.91 (2H, m), 2.69 (2H, s),3.41-3.55 (2H, m), 3.77-3.90 (2H, m), 5.15 (2H, s), 7.28-7.38 (5H, m).

(+)-APCI/MS: 248 (M⁺ +1)

Preparation 4

To a solution of (3R)-3-hydroxypyrrolidine hydrochloride (24.8 g) in amixture of dioxane (200 ml) and water (200 ml) were added successivelywith triethylamine (60 ml) and di-tert-butyl dicarbonate (48.2 g) at 0°C., which mixture was allowed to warm to ambient temperature and stirredovernight.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (400 ml), washed successively with 1N aqueous hydrochloric acid(200 ml), saturated sodium hydrogencarbonate in water (200 ml) andsaturated sodium chloride in water (200 ml×2), and dried over magnesiumsulfate.

Insoluble material was removed by filtration and the filtrate wasconcentrated in vacuo to give(3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (27.17 g).

NMR (CDCl₃, δ): 1.46 (9H, s), 1.89-2.05 (2H, m), 2.77 (1H, s), 3.30-3.50(4H, m), 4.39-4.47 (1H, m).

(+)-APCI/MS (m/z): 188 (M⁺ +1).

Preparation 5

1-tert-Butoxycarbonyl-4-piperidinol was obtained in 91.2% yield insubstantially the same manner as in Preparation 4.

NMR (DMSO-d₆, δ): 1.14-1.33 (2H, m), 1.39 (9H, s), 1.60-1.74 (2H, m),2.87-3.01 (2H, m), 3.55-3.71 (3H, m), 4.67 (1H, d, J=4.1 Hz).

Preparation 6

1-tert-Butoxycarbonyl-2-(2-hydroxyethyl)piperidine was obtained insubstantially the same manner as in Preparation 4.

NMR (CDCl₃, δ): 1.40-2.05 (8H, m), 1.47 (9H, s), 2.60-2.80 (1H, m),3.25-3.72 (2H, m), 3.75-4.05 (2H, m), 4.35-4.50 (1H, m).

Preparation 7

To a suspension of lithium aluminum hydride (2.0 g) in tetrahydrofuran(100 ml) was added dropwise a solution of1-tert-butoxycarbonyl-2-(2-hydroxyethyl)piperidine (8.0 g) intetrahydrofuran (50 ml) at ambient temperature under nitrogenatmosphere.

After stirring for 6 hours, the reaction mixture was refluxed for 3.5hours.

The reaction mixture was allowed to cool to 5° C., and water (2 ml), 4Naqueous sodium hydroxide solution (2 ml) and water (6 ml) weresuccessively added with care.

Insoluble material was removed by filtration and the filtrate wasconcentrated in vacuo to give a residue, which was chromatographed onsilica gel eluting successively with chloroform, a mixture of chloroformand methanol (10:1) and methanol.

Fractions containing desired product were collected and the solvent wasremoved under reduced pressure to give2-(2-hydroxyethyl)-1-methylpiperidine (2.47 g).

NMR (CDCl₃, δ): 1.20-1.85 (7H, m), 1.99-2.12 (2H, m), 2.20-2.35 (1H, m),2.37 (3H,s), 2.85-2.95 (1H, m), 3.65-3.76 (1H, m), 3.90-4.04 (1H, m).

(+)-APCI/MS (m/z): 144 (M⁺ +1)

Preparation 8

To a suspension of 4-hydroxypiperidine (5.0 g) and triethylamine (7.6ml) in dichloromethane (100 ml) was added dropwise propionyl chloride(4.5 ml) at -70 to -60° C. under nitrogen atmosphere.

After stirring for 1 hour, insoluble material was removed by filtrationand the filtrate was concentrated in vacuo to give a residue, to whichwas added ethyl acetate (200 ml), followed by stirring for 30 minutes.

Insoluble material was removed by filtration and the filtrate wasconcentrated in vacuo to give 4-hydroxy-1-propionylpiperidine (7.70 g).

NMR (CDCl₃, δ): 1.15 (3H, t, J=7.5 Hz), 1.37-1.59 (2H, m), 1.82-1.96(2H, m), 2.22 (2H, br-s), 2.36 (2H, q, J=7.5 Hz), 3.65-4.20 (3H, m).

(+)-AFCI/MS (m/z): 158 (M⁺ +1)

Preparation 9

To a suspension of lithium aluminum hydride (1.81 g) in tetrahydrofuran(100 ml) was added dropwise a solution of4-hydroxy-1-propionylpiperidine (5.0 g) in tetrahydrofuran (30 ml) atambient temperature under nitrogen atmosphere.

After stirring for 1 hours, the reaction mixture was refluxed for 4hours, and then which was allowed to cool to 4° C.

To the resulting mixture were successively added with care water (1.81ml), 4N aqueous sodium hydroxide solution (1.81 ml) and water (5.43 ml),which was followed by stirring for additional 1 hour.

Insoluble material was removed by filtration and the filtrate wasconcentrated in vacuo to give 4-hydroxy-1-propylpiperidine (4.37 g).

NMR (CDCl₃, δ): 0.89 (3H, t, J=7.4 Hz), 1.45-1.69 (4H, m), 1.84-2.19(5H, m), 2.24-2.33 (2H, m), 2.73-2.84 (2H, m), 3.62-3.76 (1H, m).

(+)-APCI/MS (m/z): 144 (M⁺ +1)

Preparation 10

1-Butyryl-4-hydroxypiperidine was obtained in 98.7% yield insubstantially the same manner as in Preparation 8.

NMR (CDCl₃, δ): 0.97 (3H, t, J=7.4 Hz), 1.40-1.75 (4H, m), 1.80-2.00(2H, m), 2.27-2.36 (2H, m), 2.42 (1H, br-s), 3.10-3.30 (2H, m),3.65-3.80 (1H, m), 3.85-3.98 (1H, m), 4.00-4.15 (1H, m).

(+)-APCI/MS (m/z): 172 (M⁺ +1)

Preparation 11

1-Butyl-4-hydroxypiperidine was obtained in 98.0% yield in substantiallythe same manner as in Preparation 9.

NMR (CDCl₃, δ): 0.91 (3H, t, J=7.2 Hz), 1.20-1.65 (6H, m), 1.80-2.20(5H, m), 2.25-2.35 (2H, m), 2.70-2.80 (2H, m), 3.61-3.75 (1H, m).

(+)-APCI/MS (m/z): 158 (M⁺ +1)

Preparation 12

4-Hydroxy-1-pentanoylpiperidine was obtained in 98.3% yield insubstantially the same manner as in Preparation 8.

NMR (CDCl₃, δ): 0.93 (3H, t, J=7.2 Hz), 1.20-1.70 (6H, m), 1.80-2.00(2H, m), 2.25 (1H, br-s), 2.29-2.38 (2H, m), 3.09-3.27 (2H, m),3.65-3.85 (1H, m), 3.86-4.00 (1H, m), 4.03-4.18 (1H, m).

(+)-APCI/MS (m/z): 186 (M⁺ +1)

Preparation 13

4-Hydroxy-1-pentylpiperidine was obtained in 99.4% yield insubstantially the same manner as in Preparation 9.

NMR (CDCl₃, δ): 0.89 (3H, t, J=6.4 Hz), 1.20-1.65 (8H, m), 1.85-1.95(2H, m), 2.00-2.35 (5H, m), 2.72-2.83 (2H, m), 3.50-3.75 (1H, m).

(+)-APCI/MS (m/z): 172 (M⁺ +1)

Preparation 14

1-Hexanoyl-4-hydroxypiperidine was obtained in 96.7% yield insubstantially the same manner as in Preparation 8.

NMR (CDCl₃, δ): 0.90 (3H, t, J=6.6 Hz), 1.20-1.70 (8H, m), 1.78-2.00(2H, m), 2.10 (1H, s), 2.28-2.37 (2H, m), 3.10-3.30 (2H, m), 3.65-3.82(1H, m), 3.86-3.99 (1H, m), 4.03-4.20 (1H, m).

(+)-APCI/MS (m/z): 200 (M⁺ +1)

Preparation 15

1-Hexyl-4-hydroxypiperidine was obtained in 97.2% yield in substantiallythe same manner as in Preparation 9.

NMR (CDCl₃, δ): 0.88 (3H, t, J=6.6 Hz), 1.20-1.70 (10H, m), 1.80-1.95(2H, m), 2.00-2.35 (5H, m), 2.70-2.85 (2H, m), 3.55-3.75 (1H, m).

(+)-APCI/MS (m/z): 186 (M⁺ +1)

Preparation 16

1-Acetylpiperidin-4-ol was obtained in 95.6% yield in substantially thesame manner as in Preparation 8.

NMR (DMSO-d₆, δ): 1.10-1.40 (2H, m), 1.60-1.80 (2H, m), 1.97 (3H, s),2.95 (1H, ddd, J=3.4 Hz, 9.6 Hz, 13.1 Hz), 3.05-3.19 (1H, m), 3.55-3.75(2H, m), 3.80-3.95 (1H, m), 4.72 (1H, d, J=4.1 Hz).

(+)-APCI/MS (m/z): 144 (M⁺ +1)

Preparation 17

1-Ethylpiperidin-4-ol was obtained in 87.0% yield in substantially thesame manner as in Preparation 9.

NMR (DMSO-d₆, δ): 0.96 (3H, t, J=7.2 Hz), 1.24-1.43 (2H, m), 1.60-1.75(2H, m), 1.85-2.00 (2H, m), 2.26 (2H, q, J=7.2 Hz), 2.60-2.75 (2H, m),3.33-3.50 (1H, m), 4.52 (1H, d, J=4.2 Hz).

(+)-APCI/MS (m/z): 130 (M⁺ +1)

Preparation 18

To a solution of isonipecotic acid (5 g) in a mixture of dioxane (50 ml)and water (25 ml) were successively added 38 ml of 1N aqueous sodiumhydroxide solution and di-tert-butyl dicarbonate (8.87 g) at 0° C.,which mixture was allowed to warm to ambient temperature and stirredovernight.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (200 ml) and water (100 ml).

The pH was adjusted to 2 with 2N aqueous hydrochloric acid. The organicphase was separated, and dried over magnesium sulfate.

Evaporation of the solvent gave1-tert-butoxycarbonyl-4-piperidinecarboxylic acid (8.4 g).

NMR (DMSO-d₆, δ): 1.20-1.50 (2H, m), 1.39 (9H, s), 1.70-1.90 (2H, m),2.30-2.50 (1H, m), 2.65-2.95 (2H, m), 3.83 (2H, br-d, J=13.2 Hz), 12.27(1H, br-s).

Preparation 19

To a suspension of lithium aluminum hydride (350 mg) in tetrahydrofuran(20 ml) was added dropwise a solution of1-tert-butoxycarbonyl-4-piperidinecarboxylic acid (1 g) at ambienttemperature under nitrogen atmosphere.

After stirring for 24 hours, the reaction mixture was allowed to cool to0° C., and water (0.35 ml), 4N aqueous sodium hydroxide solution (0.35ml) and water (1.05 ml) were successively added with care.

Insoluble material was removed by filtration and the filtrate wasconcentrated in vacuo to give 1-m ethyl-4-piperidinemethanol (600 mg).

NMR (DMSO-d₆, δ): 1.00-1.80 (7H, m), 2.12 (3H, s), 2.72 (2H, br-d,J=11.5 Hz), 3.22 (2H, t, J=5.6 Hz), 4.40 (1H, t, J=5.3 Hz).

(+)-APCI/MS (m/z): 144 (M⁺ +1)

Preparation 20

To a stirred suspension of sodium hydride (238 mg) in tetrahydrofuran(50 ml) was added dropwise triethylphosphonoacetate (1.2 ml) at ambienttemperature under nitrogen atmosphere.

After stirring for 30 minutes, to the reaction mixture was addeddropwise 1-tert-butoxycarbonyl-4-piperidone (1 g), and the mixture wasstirred overnight. To the stirred reaction mixture was added water (1ml).

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate and washed successively with water (100 ml) and brine (100 ml),and dried over anhydrous magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed onsilica gel eluting with a mixture of n-hexane and ethyl acetate (4:1) togive 1-tert-butoxycarbonyl-4-ethoxycarbonylmethylenepiperidine (1.19 g).

NMR (DMSO-d₆, δ): 1.17 (3H, t, J=7.1 Hz), 1.38 (9H, s), 2.20-2.30 (2H,m), 2.79-2.85 (2H, m), 3.34-3.44 (4H, m), 4.07 (2H, q, J=7.1 Hz), 5.75(1H, s).

Preparation 21

A mixture of 1-tert-butoxycarbonyl-4-ethoxycarbonylmethylenepiperidine(3 g) and 10% palladium on carbon (50% wet, 600 mg) in methanol (150 ml)was stirred for 2 hours under hydrogen atmosphere.

The catalyst was removed by filtration. Evaporation of the solvent gave1-tert-butoxycarbonyl-4-ethoxycarbonylmethylpiperidine (3.12 g).

NMR (DMSO-d₆, δ): 0.90-1.17 (2H, m), 1.17 (3H, t, J=7.1 Hz), 1.38 (9H,s), 1.55-1.95 (3H, m), 2.23 (2H, d, J=7.0 Hz), 2.55-2.85 (2H, m), 3.90(2H, br-d, J=13.3 Hz), 4.05 (2H, q, J=7.1 Hz).

Preparation 22

1-Methyl-4-piperidineethanol was obtained in 82.0% yield insubstantially the same manner as in Preparation 19.

NMR (DMSO-d₆, δ): 1.00-1.40 (5H, m), 1.58 (2H, br-d, J=12.4 Hz),1.70-1.90 (2H, m), 2.10 (3H, s), 2.70 (2H, br-d, J=11.6 Hz), 3.41 (2H,q, J=6.5 Hz), 4.31 (1H, t, J=5.1 Hz).

(+)-APCI/MS (m/z): 130 (M⁺ +1)

EXAMPLE 1

A mixture of3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(0.50 g) and bromoacetaldehyde diethyl acetal (0.54 ml) in a mixture ofmethanol (2.5 ml) and chloroform (5 ml) was refluxed for 54 hours. Afterevaporating the solvent, the residue was chromatographed on silica gel(40 ml) using a mixture of chloroform and ethyl acetate (20:1). Thedesired fractions were collected and evaporated in vacuo. The residuewas recrystallized from a mixture of ethyl acetate and n-hexane to give3-[3-oxo-2-(2-thiazolylmethyl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(0.23 g) as yellow needles.

mp: 130.0-132.0° C. (EtOAc-n-hexane)

IR (Nujol): 1665, 1630, 1590, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 5.68 (2H, s), 6.96 (1H, d, J=9.7 Hz), 7.08 (1H, dt,J=1.3 Hz, 6.9 Hz), 7.10 (1H, d, J=9.7 Hz), 7.37-7.49 (4H, m), 7.58-7.63(2H, m), 7.75 (1H, d, J=3.3 Hz), 7.84 (1H, d, J=3.3 Hz), 7.89 (1H, d,J=8.9 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 386 (M+H)⁺

Anal. Calcd. for C₂₁ H₁₅ N₅ OS.1/4H₂ O: C 64.44, H 4.03, N 17.89

Found: C 64.05, H 3.85, N 17.57

EXAMPLE 2

A stirred mixture of3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.0g), 4-chloro-1-methylpiperidine hydrochloride (1.24 g) and sodiumhydride (610 mg, 60% dispersion in mineral oil) in N,N-dimethylformamide(20 ml) was heated at 115° C., and stirred for 1 day.

The reaction mixture was cooled to ambient temperature and water wasadded thereto.

Evaporation of the solvent gave a residue, which was dissolved inchloroform (300 ml) and washed successively with water (20 ml×2),saturated sodium hydrogencarbonate in water (20 ml) and saturated sodiumchloride in water (20 ml), and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed onsilica gel (100 ml) eluting successively with chloroform and a mixtureof chloroform and methanol (50:1→40:1→10:1). Fractions containingdesired product were collected and the solvent was removed in vacuo togive a product, which was recrystallized from 50% aqueous ethanol togive3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(471 mg).

mp: 139.0-140.0° C. (aq. EtOH)

FT IR (KBr): 1660.4, 1589.1, 1531.2, 1496.5, 1465.6 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-2.10 (6H, m), 2.20 (3H, s), 2.80-3.00 (2H, m),4.70-4.90 (1H, m), 6.87 (1H, d, J=9.7 Hz), 7.05-7.13 (2H, m), 7.40-7:65(6H, m), 7.90 (1H, d, J=8.9 Hz), 8.83 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 386 (M+1)

Anal. Calcd. for C₂₃ H₂₃ N₅ O.H₂ O: C 68.47, H 6.25, N 17.36

Found: C 68.71, H 6.08, N 17.37

EXAMPLE 3

To a stirred mixture of3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (30g), 1-methyl-4-hydroxypiperidine (15.58 g) and triphenylphosphine (40.94g) in tetrahydrofuran (1.2 l) was added dropwise diethylazodicarboxylate (24.58 ml) at -5 to 0° C. under nitrogen atmosphere.

The reaction mixture was allowed to warm to ambient temperature andstirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (2 l) and extracted two times with 300 ml of 2N aqueoushydrochloric acid. Aqueous phases were combined and the pH was adjustedto 10.7 with 30% aqueous sodium hydroxide solution while keeping thetemperature at 5 to 15° C.

Insoluble material was collected by filtration, washed with 500 ml ofwater and dried to give a crude product.

The crude product was dissolved in chloroform, which was chromatographedon silica gel (800 g) eluting successively with ethyl acetate,chloroform and a mixture of chloroform and methanol (40:1).

Fractions containing desired product were collected and the solvent wasremoved in vacuo to give crude crystals, which were recrystallized from50% aqueous ethanol to give3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(19.36 g).

EXAMPLE 4

To a stirred solution of3-(3-oxo-2,3-dihydropyridazin-6yl)-2-phenylpyrazolo[1,5-a]pyridine (1.0g), 1-methyl-4-hydroxypiperidine (520 mg) and triphenylphosphine (1.37g) in tetrahydrofuran (40 ml) was added dropwise diisopropylazodicarboxylate (1.03 ml) at -5 to 0° C. under nitrogen atmosphere.

The reaction mixture was allowed to warm to ambient temperature andstirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (100 ml) and extracted two times with 50 ml of 6N aqueoushydrochloric acid. Aqueous phases were combined and the pH was adjustedto 10.0 with 30% aqueous sodium hydroxide solution while keeping thetemperature at 5 to 15° C.

Insoluble material was collected by filtration, washed with water anddried under reduced pressure to give a crude product.

The crude product was dissolved in chloroform, which was chromatographedon silica gel (75 g) eluting with a mixture of chloroform and methanol(40:1).

Fractions containing desired product were collected and the solvent wasremoved in vacuo to give crude crystals, which were recrystallized from50% aqueous ethanol to give3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(736 mg).

EXAMPLE 5

To a suspension of3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(5.7 g), in ethanol (30 ml) was added 25% hydrochloric acid in ethanol(5 ml), which mixture was stirred overnight at ambient temperature.

Resulting precipitates were collected by filtration, washed with ethanoland dried under reduced pressure to give3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyzazolo[1,5-a]pyridinehydrochloride (5.77 g).

mp: 271.0-274.0° C. (EtOH)

FT IR (KBr): 1658.5, 1587.1, 1525.4, 1490.7, 1467.6, 1419.4 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-2.15 (2H, m), 2.25-2.45 (2H, m), 2.76 (3H, s),3.15-3.35 (2H, m), 3.45-3.60 (2H, m), 5.05-5.25 (1H, m), 6.89 (1H, d,J=9.7 Hz), 7.04-7.14 (2H, m), 7.47-7.64 (6H, m), 8.10 (1H, d, J=8.9 Hz),8.83 (1H, d, J=6.9 Hz), 10.72 (1H, br-s).

(+)FAB-MS (m/z): 386 (M⁺ +1)

Anal: Calcd. for C₂₃ H₂₅ ClN₅ O.3/2 H₂ O C: 61.53, H: 6.06, N: 15.60

Found: C: 61.39, H: 5.98, N: 15.60

EXAMPLE 6

3-[2-(1-tert-Butoxycarbonylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 45.9% yield in substantially the same manner as inExample 3.

mp: 152.0-153.0° C. (EtOH)

FT IR (KBr): 1675.8, 1660.4, 1589.1, 1529.3, 1469.5, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.41(9H, s), 1.60-1.90 (4H, m), 2.80-3.05 (2H, m),4.00-4.15 (2H, m), 4.95-5.15 (1H, m), 6.91 (1H, d, J=9.7 Hz), 7.08 (1H,dt, J=1.3 Hz and 6.9 Hz), 7.18 (1H, d, J=9.7 Hz), 7.35-7.55 (4H, m),7.56-7.62 (2H, m), 7.85 (1H, d, J=8.9 Hz), 8.83 (1H, d, J=6.9 Hz).

Anal: Calcd. for C₂₇ H₂₉ N₅ O₃.H₂ O C: 66.24, H: 6.38, N: 14.30

Found: C: 66.66, H: 6.26, N: 14.24

EXAMPLE 7

A mixture of3-[2-((3S)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine(2.4 g) in 6N-aqueous hydrochloric acid (50 ml) was refluxed for 4.5hours.

The reaction mixture was cooled and the solvent was removed in vacuo.

To the resultant residue were added ethanol (15 ml) and 25% hydrochloricacid in ethanol (5 ml), which mixture was stirred overnight at ambienttemperature.

Resulting precipitates were collected by filtration, washed with ethanoland dried under reduced pressure to give3-[3-oxo-2-((3S)-pyrrolidin-3-yl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinehydrochloride (1.8 g).

mp: 211.0-212.5° C. (EtOH)

FT IR (KBr): 1662.3, 1589.1, 1519.6, 1492.6, 1465.6, 1413.6 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-2.40 (2H, m), 3.19-3.30 (2H, m), 3.41 (1H, dd,J=5.2 Hz and 12.3 Hz), 3.62 (1H, dd, J=7.6 Hz and 12.3 Hz), 5.56-5.65(1H, m), 6.94 (1H, d, J=9.7 Hz), 7.09 (1H, dt, J=1.3 Hz and 6.9 Hz),7.19 (1H, d, J=9.7 Hz), 7.41-7.52 (4H, m), 7.60-7.65 (2H, m), 7.93 (1H,d, J=8.9 Hz), 8.83 (1H, d, J=6.9 Hz), 9.46 (2H, br-s).

(+)-FAB/MS (m/z): 358 (M⁺ +1)

Anal. Calcd. for C₂₁ H₂₀ ClN₅ O.11/4H₂ O C 60.58, H 5.45, N 16.82

Found: C 60.31, H 5.47, N 16.62

EXAMPLE 8

3-[3-Oxo-2-(piperidin-4-yl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinehydrochloride was obtained in 79.5% yield in substantially the samemanner as in Example 7.

mp: over 290° C. (EtOH)

FT IR (KBr): 1658.5, 1587.1, 1521.6, 1492.6, 1465.6, 1415.5 cm⁻¹

NMR (DMSO-d₆, δ): 1.95-2.40 (4H, m), 3.00-3.25 (2H, m), 3.30-3.45 (2H,m), 5.10-5.30 (1H, m), 6.89 (1H, d, J=9.7 Hz), 7.05-7.15 (2H, m),7.45-7.64(6H, m), 8.04 (1H, d, J=8.9 Hz), 8.83 (1H, d, J=6.9 Hz), 9.16(2H, br-s).

(+)-FAB/MS (m/z): 372 (M⁺ +1)

Anal: Calcd. for C₂₂ H₂₂ ClN₅ O.3/4H₂ O

C: 62.70, H: 5.62, N: 16.62

Found: C: 62.76, H: 5.72, N: 16.53

EXAMPLE 9

To a stirred mixture of3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(3.34 g), (3R)-1-tertbutoxycarbonyl-3-hydroxypyrrolidine (2.6 g) andtriphenylphosphine (4.55 g) in tetrahydrofuran (100 ml) was addeddropwise diethyl azodicarboxylate (2.73 ml) at 0 to 5° C. under nitrogenatmosphere.

The reaction mixture was allowed to warm to ambient temperature andstirred overnight.

Evaporation of the solvent gave a residue, to which was added 6N aqueoushydrochloric acid (100 ml), and the mixture was refluxed for 8 hours.

The reaction mixture was cooled and washed with ethyl acetate (200ml×2).

The pH of the aqueous phase was adjusted to 12 with 30% aqueous sodiumhydroxide solution while keeping the temperature at 5 to 15° C.

The resultant was extracted with chloroform (200 ml×2) and organicphases were combined and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed onsilica gel eluting successively with chloroform and a mixture ofchloroform and methanol (40:1→20:1 →10:1).

Fractions containing desired product were collected and the solvent wasremoved in vacuo to give a crude product, which was recrystallized fromethanol to give3-[3-oxo-2-((3S)-pyrrolidin-3-yl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(2.84 g).

mp: 144.0-145.5° C. (EtOH)

FT IR (KBr): 1658.5, 1585.2, 1525.4, 1490.7, 1465.6, 1415.5 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.20 (2H, m), 2.75-3.00 (3H, m), 3.12 (1H, dd,J=7.2 Hz and 11.7 Hz), 5.37-5.47 (1H, m), 6.87 (1H, d, J=9.6 Hz), 7.07(1H, dt, J=1.3 Hz and 6.9 Hz), 7.18 (1H, d, J=9.6 Hz), 7.40-7.62 (6H,m), 7.89 (1H, d, J=8.9 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 358 (M⁺ +1)

Anal. Calcd. for C₂₁ H₁₉ N₅ O.2/3H₂ O C 68.28, H 5.55, N 18.96

Found: C 68.47, H 5.28, N 18.90

EXAMPLE 10

3-[3-Oxo-2-(piperidin-4-yl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 62.2% yield in substantially the same manner as inExample 9.

mp: 115.0-117.0° C. (aq. EtOH)

FT IR (KBr): 1656.6, 1585.2, 1529.3, 1494.6, 1463.7, 1421.3 cm⁻¹

NMR (DMSO-d₆, δ): 1.70-1.85 (4H, m), 2.50-2.70 (2H, m), 3.00-3.10 (2H,m), 4.80-5.00 (1H, m), 6.87 (1H, d, J=9.6 Hz), 7.05-7.13 (2H, m),7.43-7.63(6H, m), 7.91 (1H, d, J=8.9 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 372 (M⁺ +1)

Anal: Calcd. for C₂₂ H₂₁ N₅ O.21/4H₂ O C: 64.21, H: 6.25, N: 17.02

Found: C: 64.26, H: 6.28, N: 16.94

EXAMPLE 11

3-[2-(1-Ethylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 28.1% yield in substantially the same manner as inExample 3.

mp: 134.0-135.0° C. (50% aq. EtOH)

IR (KBr): 1660.4, 1589.1, 1529.3, 1492.6, 1465.6, 1415.5 cm⁻¹

NMR (DMSO-d₆, δ): 1.01 (3H, t, J=7.1 Hz), 1.80-2.15 (6H, m), 2.36 (2H,q, J=7.1 Hz), 2.90-3.10 (2H, m), 4.70-4.90 (1H, m), 6.87 (1H, d, J=9.7Hz), 7.05-7.15 (2H, m), 7.45-7.60 (6H, m), 7.89 (1H, d, J=8.9 Hz), 8.83(1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 400 (M⁺ +1)

Anal: Calcd. for C₂₄ H₂₅ N₅ O.1/10H₂ O C: 70.57, H: 6.42, N: 17.14

Found: C: 71.02, H: 6.35, N: 17.07

EXAMPLE 12

3-[2-(1-Propylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 44.7% yield in substantially the same manner as inExample 3.

mp: 104.0-106.0° C. (50% aq. EtOH)

IR (KBr): 1656.6, 1589.1, 1531.2, 1467.6, 1417.4, 1290.1 cm⁻¹

NMR (DMSO-d₆, δ): 0.86 (3H, t, J=7.3 Hz), 1.35-1.55 (2H, m), 1.70-2.35(8H, m), 2.90-3.05 (2H, m), 4.70-4.90 (1H, m), 6.89 (1H, d, J=9.7 Hz),7.05-7.30 (2H, m), 7.40-7.60 (6H, m), 7.88 (1H, d, J=8.9 Hz), 8.83 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 414 (m⁺ +1)

Anal. Calcd. for C₂₅ H₂₇ N₅ O.1/10H₂ O C 72.58, H 6.60, N 16.86

found: C 72.61, H 6.58, N 16.94

EXAMPLE 13

3-[2-(1-Butylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 44.6% yield in substantially the same manner as inExample 3.

mp: 106.0-108.0° C. (50% aq. EtOH)

IR (KBr): 1656.6, 1591.0, 1538.9, 1465.6, 1419.4, 1342.2 cm⁻¹

NMR (CDCl₃, δ): 0.94 (3H, t, J=7.1 Hz), 1.20-1.65 (4H, m), 1.90-2.50(8H, m), 3.05-3.20 (2H, m), 4.95-5.15 (1H, m), 6.74 (1H, d, J=9.6 Hz),6.88-6.96 (1H, m), 6.98 (1H, d, J=9.6 Hz), 7.28-7.40 (1H, m), 7.43-7.48(3H, m), 7.55-7.62 (2H, m), 8.01 (1H, d, J=8.9 Hz), 8.52 (1H, d, J=6.9Hz).

(+)-APCI/MS (m/z): 428 (M⁺ +1)

Anal. Calcd. for C₂₆ H₂₉ N₅ O.1/2H₂ O C 71.53, H 6.93, N 16.04

found: C 71.39, H 6.87, N 15.99

EXAMPLE 14

3-[3-Oxo-2-(1-pentylpiperidin-4-yl)-2,3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 38.8% yield in substantially the same manner as inExample 3.

mp: 105.5-106.0° C. (aq. EtOH)

FT IR (KBr): 1660.4, 1589.1, 1531.2, 1496.5, 1465.6, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 0.83-0.91 (3H, m), 1.20-1.45 (6H, m), 1.75-2.15 (6H,m), 2.20-2.35 (2H, m), 2.90-3.05 (2H, m), 4.70-4,90 (1H, m), 6.88 (1H,d, J=9.6 Hz), 7.05-7.15 (2H, m), 7.57-7.60 (2H, m), 7.88 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 442 (M⁺ +1)

Anal. Calcd. for C₂₇ H₃₁ N₅ O.1/4H₂ O C 72.70, H 7.12, N 15.70

found: C 72.73, H 7.10, N 15.72

EXAMPLE 15

3-[2-(1-Hexylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 26.3% yield in substantially the same manner as inExample 3.

mp: 106.0-106.5° C. (aq. EtOH)

FT IR (KBr): 1660.4, 1589.1, 1531.2, 1463.7, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 0.82-0.90 (3H, m), 1.20-1.55 (8H, m), 1.70-2.15 (6H,m), 2.20-2.35 (2H, m), 2.90-3.05 (2H, m), 4.70-4,90 (1H, m), 6.88 (1H,d, J=9.6 Hz), 7.00-7.15 (2H, m), 7.40-7.65 (6H, m), 7.88 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 456 (M⁺ +1)

Anal. Calcd. for C₂₈ H₃₃ N₅ O.1/8H₂ O C 73.45, H 7.32, N 15.30

found: C 73.35, H 7.39, N 15.28

EXAMPLE 16

To a suspension of sodium hydride (65 mg, 60% dispersion in mineral oil)in N,N'-dimethylformamide (20 ml) was added dropwise3-[2-(piperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(500 mg) at 25° C. under nitrogen atmosphere, which was followed bystirring for 30 minutes.

To the reaction mixture was added isopropyl iodide (940 mg) and themixture was stirred for additional 18 hours.

To the resulting mixture were added excess triethylamine and water.Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (100 ml) and washed with 1N-aqueous hydrochloric acid. Theaqueous layer was adjusted to pH 10-12 with 4N-aqueous sodium hydroxidesolution and extracted with ethyl acetate (100 ml). The organic layerwas separated, washed with water (100 ml) and dried over magnesiumsulfate. Evaporation of the solvent gave a residue, which wasrecrystallized from 50% aqueous ethanol to give3-[2-(1-isopropylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(350 mg).

mp: 157.5-158.3° C. (50% aq. EtOH)

IR (KBr): 1660.4, 1589.1, 1531.2, 1467.6, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 0.98 (6H, d, J=6.5 Hz), 1.75-2.00 (4H, m), 2.20-2.40(2H, m), 2.65-2.95 (3H, m), 4.70-4.90 (1H, m), 6.87 (1H, q, J=9.6 Hz),7.05-7.13 (2H, m) 7.40-7.60 (6H, m), 7.88 (1H, d, J=8.9 Hz), 8.83 (1, d,J=7.0 Hz).

(+)-APCI/MS (m/z): 414 (M⁺ +1)

EXAMPLE 17

3-[2-(1-Methylpiperidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 31.0% yield in substantially the same manner as inExample 3.

mp: 126.0-127.0°C. (50% aq. EtOH)

IR (KBr): 1658.5, 1587.1, 1529.3, 1465.6, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-2.10 (6H, m), 2.18 (3H, s), 2.70-2.95 (2H, m),4.80-5.00 (1H, m), 6.89 (1H, d, J=9.6 Hz), 7.00-7.15 (1H, m), 7.19 (1H,d, J=9.6 Hz), 7.40-7.65 (6H, m), 7.88 (1H, d, J=8.9 Hz), 8.82 (1H, d,J=6.9 Hz).

(+)-APCI/MS (m/z): 386.1 (M⁺ +1)

Anal. Calcd. for C₂₃ H₂₃ N₅ O.1/2 H₂ O C 65.54, H 6.46, N 16.61

found: C 65.75, H 6.39, N 16.56

EXAMPLE 18

3-[2-(1-Benzylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 60.7% yield in substantially the same manner as inExample 3.

mp: 184.1-185.3° C. (50% aq. EtOH)

IR (KBr): 1662.3, 1589.1, 1525.4, 1490.7, 1459.8 1415.5 cm⁻¹

NMR (DMSO-d₆, δ): 1.70-2.20 (6H, m), 2.93 (2H, br-d, J=12.4 Hz), 3.51(2H, s), 4.70-4.90 (1H, m), 6.88 (1H, d, J=9.6 Hz), 7.00-7.17 (2H, m),7.20-7.65 (1H, m), 7.88 (1H, d, J=8.8 Hz), 8.84 (1H, d, J=7.0 Hz).

(+)-APCI/MS (m/z): 462 (M⁺ +1)

Anal. Calcd. for C₂₉ H₂₇ N₅ O.1/2H₂ O C 74.02, H 6.00, N 14.88

found: C 74.37, H 6.08, N 15.36

EXAMPLE 19

To a stirred solution of3-(3-oxo-2-(piperidin-4-yl)-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(0.5 g) in pyridine (30 ml) was added dropwise acetic anhydride (1.28ml) at ambient temperature.

The reaction mixture was stirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (100 ml) and washed successively with 2N aqueous hydrochloricacid (100 ml) and saturated sodium chloride in water (100 ml), and driedover magnesium sulfate.

Insoluble material was removed by filtration. The filtrate wasconcentrated in vacuo to give3-[2-(1-acetylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(0.5 g).

mp: 114.0-116.9° C. (EtOH)

IR (KBr): 1656.6, 1627.6, 1585.2, 1531.2, 1457.9, 1427.1 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-2.00 (4H, m), 2.02 (3H, s), 2.60-2.80 (1H, m),3.15-3.35 (1H, m), 3.90 (1H, br-d, J=12.2 Hz), 4.49 (1H, br-d, J=13.2Hz), 5.00-5.20 (1H, m), 6.92 (1H, d, J=9.6 Hz), 7.03-7.12 (1H, m), 7.20(1H, d, J=9.6 Hz), 7.40-7.60 (6H, m), 7.84 (1H, d, J=8.9 Hz), 8.83 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 414 (M⁺ +1)

EXAMPLE 20

To a stirred mixture of3-[3-oxo-2-(piperidin-4-yl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(500 mg), potassium tert-butoxide (182 mg) and 18-crown-6-ether (34 mg)in tetrahydrofuran (20 ml) was added methyl iodide (0.17 ml) at ambienttemperature, which mixture was stirred overnight at that temperature.

An insoluble material appeared in the reaction mixture, which wascollected by filtration. The crude solid was recrystallized from ethanolto give3-[2-(1,1-dimethyl-4-piperidinio)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridineiodide (730 mg).

mp: 225.0-226.5° C. (hexane)

IR (KBr): 1666.2, 1631.5, 1594.8, 1529.3, 1465.6 cm⁻¹

NMR (DMSO-d₆, δ): 1.95-2.30 (4H, m), 2.99 (3H, s), 3.17 (3H, s),3.45-3.80 (4H, m), 5.00-5.20 (1H, m), 6.98 (1H, d, J=9.7 Hz), 7.06-7.14(1H, m), 7.32 (1H, d, J=9.7Hz), 7.40-7.65 (6H, m), 7.91 (1H, d, J=8.9Hz), 8.85 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 400 (M⁺)

EXAMPLE 21

3-[2-((3S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 60.9% yield in substantially the same manner as inExample 3.

mp: 165.5-167.0° C. (EtOH)

FT IR (KBr): 1679.7, 1664.3, 1591.0, 1517.7, 1483.0, 1457.9, 1403.9 cm⁻¹

NMR (DMSO-d₆, δ): 1.30-1.40(9H, m), 2.10-2.30(2H, m), 3.34-3.80(4H, m),5.45-5.60(1H, m), 6.89(1H, d, J=9.7 Hz), 7.04-7.11(1H, m), 7.13(1H, d,J=9.7 Hz), 7.34-7.64(6H, m), 7.82(1H, d, J=8.9 Hz), 8.82(1H, d, J=6.9Hz).

EXAMPLE 22

3-[3-Oxo-2-(3-quinuclidinyl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 7.3% yield in substantially the same manner as inExample 3.

mp: 191.0-192.7° C. (50% aq. EtOH)

IR (KBr): 1660.4, 1591.0, 1535.1, 1467.6, 1411.6 cm⁻¹

NMR (CDCl₃, δ): 1.20-1.50 (1H, m), 1.55-2.00 (3H, m), 2.15-2.35 (1H, m),2.70-3.20 (4H, m), 3.21-3.35 (1H, m), 3.59 (1H, dd, J=5.6 Hz and 13.9Hz), 5.15-5.25 (1H, m), 6.80 (1H, d, J=9.6 Hz), 6.87-6.96 (1H, m), 7.07(1H, d, J=9.6 Hz), 7.27-7.61 (6H, m), 7.91 (1H, d, J=8.9 Hz), 8.55 (1H,d, J=7.0 Hz).

(+)-APCI/MS (m/z): 398 (M⁺ +1)

EXAMPLE 23

3-[2-(1-Methylpiperidin-3-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 52.1% yield in substantially the same manner as inExample 3.

mp: 159.0-160.0° C. (50% aq. EtOH)

IR (KBr): 1658.5, 1587.1, 1529.3, 1465.6 cm⁻¹

NMR (DMSO-d₆, δ): 0.90-1.10 (1H, m), 1.30-2.00 (5H, m), 2.05-2.30 (1H,m), 2.13 (3H, s), 2.50-2.60 (2H, m), 3.94-4.15 (2H, m), 6.87 (1H, d,J=9.6 Hz), 7.03-7.13 (2H, m), 7.40-7.65 (6H, m), 7.92 (1H, d, J=8.9 Hz),8.82 (1H, d, J=6.9 Hz).

Anal. Calcd. for C₂₄ H₂₅ N₅ O.3/10H₂ O C 71.19, H 6.37, N 17.30

Found: C 71.40, H 6.34, N 17.30

(+)-APCI/MS (m/z): 400.2 (M⁺ +1)

EXAMPLE 24

3-[2-(1-Methylpiperidin-2-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 58.6% yield in substantially the same manner as inExample 3.

mp: 154.0-155.0° C. (50% aq. EtOH)

IR (KBr) 1662.3, 1587.1, 1527.3, 1498.4, 1463.7 cm⁻¹

NMR (DMSO-d₆, δ).1.10-1.70 (6H, m), 2.05-2.20 (1H, m), 2.29 (3H, s),2.40-2.60 (1H, m), 2.70-2.85 (1H, m), 4.04 (1H, dd, J=4.7 Hz and 12.9Hz), 4.44 (1H, dd, J=4.7 Hz and 12.9 Hz), 6.87 (1H, d, J=9.6 Hz),7.00-7.15 (2H, m), 7.40-7.65 (6H, m), 7.98 (1H, d, J=8.9 Hz), 8.82 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 400.2 (M⁺ +1)

Anal. Calcd. for C₂₄ H₂₅ N₅ O C 72.16, H 6.31, N 17.53

Found: C 72.30, H 6.41, N 17.53

EXAMPLE 25

3-[2-{2-(1-Methylpiperidin-2-yl)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 91.0% yield in substantially the same manner as inExample 3.

mp: 113.5-116.0° C. (EtOH-n-Hexane)

FT IR (KBr): 1666.2, 1633.4, 1589.1, 1527.3, 1496.5, 1463.7, 1419.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.10-1.75 (6H, m), 1.80-2.05 (4H, m), 2.18 (3H, s),2.76 (1H, br-d, J=11.4 Hz), 4.10-4.21 (2H, m), 6.87 (1H, d, J=9.6 Hz),7.03-7.13 (1H, m), 7.12 (1H, d, J=9.6 Hz), 7.39-7.63 (6H, m), 7.94 (1H,d, J=8.9 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 414 (M⁺ +1)

Anal. Calcd. for C₂₅ H₂₇ N₅ O.1/8H₂ O C 72.22, H 6.61, N 16.84

Found: C 72.03, H 6.55, N 16.81

EXAMPLE 26

3-[3-Oxo-2-[2-(piperidin-2-yl)ethyl]-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 33.3% yield in substantially the same manner as inExample 9.

mp: 124.4-125.4 (50% aq. EtOH)

IR (KBr): 1662.3, 1585.2, 1527.3, 1496.5, 1463.7, 1446.4, 1421.3 cm⁻¹

NMR (CDCl₃, δ): 1.15-2.20 (8H, m), 2.50-2.70 (2H, m), 3.13 (1H, br-d,J=12.0 Hz), 4.19-4.33 (1H, m), 4.40-4.55 (1H, m), 6.76 (1H, d, J=9.6Hz), 6.90-6.97 (1H, m), 7.03 (1H, d, J=9.6 Hz), 7.30-7.65 (6H, m), 7.99(1H, d, J=9.0 Hz), 8.54 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 400 (M⁺ +1)

Anal. Calcd. for C₂₄ H₂₅ N₅ O.H₂ O C 69.04, H 6.52, N 16.77

Found: C 69.53, H 6.33, N 16.83

EXAMPLE 27

3-[2-(1-Methylpiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 7.9% yield in substantially the same manner as inExample 3.

mp: 179.5-181.0° C. (EtOH)

IR (KBr): 1656.6, 1587.1, 1525.4, 1490.7, 1450.2, 1419.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.15-1.45 (2H, m), 1.50-1.65 (2H, m), 1.70-1.95 (3H,m), 2.14 (3H, s), 2.74 (2H, br-d, J=10.9 Hz), 4.02 (2H, d, J=7.1 Hz),6.88 (2H, d, J=9.6 Hz), 7.00-7.20 (2H, m), 7.40-7.65 (6H, m), 7.90 (1H,d, J=8.9 Hz), 8.83 (1H, d, J=7.0 Hz).

(+)-APCI/MS (m/z): 400 (M⁺ 1)

EXAMPLE 28

To a stirred mixture of3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.7g), 1-methyl-4-piperidineethanol (1.41 g) and triphenylphosphine (3.19g) in tetrahydrofuran (60 ml) was added dropwise diethylazodicarboxylate (1.92 ml) at 0 to 5° C. under nitrogen atmosphere.

The reaction mixture was allowed to warm to ambient temperature andstirred overnight.

Evaporation of the solvent gave a residue, to which was added 2N aqueoushydrochloric acid, and the mixture was under stirring for 1 hour.

The reaction mixture was washed with ethyl acetate.

Aqueous phase was separated. The pH of the aqueous phase was adjusted to12 with 15% aqueous sodium hydroxide solution while keeping thetemperature at 5 to 15° C. The resulting solution was extracted withethyl acetate.

Organic phase was separated, washed with water and dried over magnesiumsulfate.

Evaporation of the solvent gave a residue, which was added in ethanol (2ml). 25% Hydrochloric acid in ethanol (1 ml) was added thereto and themixture was stirred overnight.

Insoluble material was collected and washed with ethanol to give3-[2-(1-methylpiperidin-4-yl)ethyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinehydrochloride (2.93 g).

mp: over 250° C. (50% aq. EtOH)

IR (KBr): 1654.6, 1583.3, 1527.3, 1467.6, 1417.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.30-2.00 (7H, m), 2.69 (3H, s), 2.75-3.00 (2H, m),3.20-3.50 (2H, m), 4.17 (2H, t, J=6.8 Hz), 6.89 (1H, d, J=9.6 Hz),7.05-7.18 (2H, m), 7.40-7.65 (6H, m), 7.92 (1H, d, J=8.9 Hz), 8.83 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 414 (M³⁰ +1)

Anal. Calcd. for C₂₅ H₂₈ ClN₅ O.1/10H₂ O C 66.46, H 6.29, N 15.50

Found: C 66.18, H 6.34 N 15.34

EXAMPLE 29

To a stirred solution of3-[2-(1-methylpiperidin-3-yl)-methyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(300 mg) in 1,2-dichloroethane (50 ml) was added dropwise 1-chloroethylchloroformate (324 μl).

The reaction mixture was refluxed under stirring for 16 hours.

Evaporation of the solvent gave a residue, which was dissolved in ethylacetate (100 ml) and extracted with 100 ml of 2N aqueous hydrochloricacid. Aqueous phase was separated, and the pH was adjusted to 12 with30% aqueous sodium hydroxide solution while keeping the temperature at 5to 15° C.

This aqueous phase was extracted with ethyl acetate (100 ml). Theorganic phase was washed with saturated sodium chloride in water (100ml), and dried over magnesium sulfate.

Evaporation of the solvent gave a crude product. The crude product wasdissolved in chloroform, which solution was chromatographed on silicagel eluting with a mixture of chloroform and methanol (40:1).

Fractions containing desired product were collected and the solvent wasremoved in vacua to give a crude solid, which was recrystallized from50% aqueous ethanol to give3-[3-oxo-2-(piperidin-3-yl)methyl-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(75 mg).

mp: 250.0-251.3° C. (EtOH)

IR (KBr): 1656.6, 1587.1, 1525.4, 1465.6, 1419.4 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-1.80 (4H, m), 2.10-2.50 (1H, m), 2.55-2.80 (2H,m), 3.00-3.30 (3H, m), 4.08 (2H, d, J=7.1 Hz), 6.90 (1H, d, J=9.7 Hz),7.00-7.15 (2H, m), 7.40-7.65 (6H, m), 7.95 (1H, d, J=8.9 Hz), 8.83 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 386 (M⁺ +1)

EXAMPLE 30

3-[2-{(Piperidin-2-yl)methyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 17.3% yield in substantially the same manner as inExample 29.

mp: 141.0-142.5° C. (50% aq. EtOH)

IR (KBr): 1666.2, 1633.4, 1591.0, 1527.3, 1494.6 cm⁻¹

NMR (DMSO-d₆, δ): 0.86-1.80 (6H, m), 2.40-2.60 (1H, m), 2.90-3.10 (3H,m), 4.05 (2H, d, J=6.1 Hz), 6.87 (1H, d, J=9.6 Hz), 7.00-7.15 (2H, m),7.40-7.65 (6H, m), 7.97 (1H, d, J=9.0 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 386 (M⁺ +1)

Anal. Calcd. for C₂₃ H₂₃ N₅ O.1/2H₂ O C 70.03, H 5.88, N 17.75

Found: C 70.31, H 6.12, N 18.19

EXAMPLE 31

3-[2-{((2S)-1-Methylpyrrolidin-2-yl)methyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 74.6% yield in substantially the same manner as inExample 3.

mp: 114.5-117.0° C. (n-Hexane-CHCl₃)

FT IR (KBr): 1664.3, 1635.3, 1589.1, 1529.3, 1496.5, 1463.7, 1423.2 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-2.00 (4H, m), 2.15-2.30 (1H, m), 2.30 (3H, s),2.60-2.80 (1H, m), 2.90-3.10 (1H, m), 4.05 (1H, dd, J=7.2 Hz and 12.7Hz), 4.27 (1H, dd, J=4.6 Hz and 12.7 Hz), 6.88 (1H, d, J=9.6 Hz),7.00-7.14 (2H, m), 7.40-7.60 (6H, m), 8.00 (1H, d, J=8.9 Hz), 8.83 (1H,d, J=6.9 Hz).

(+)-APCI/MS (m/z): 386 (M⁺ +1)

Anal. Calcd. for C₂₃ H₂₃ N₅ O.1/2H₂ O C 70.03, H 6.13, N 17.75

Found: C 70.06, H 5.97, N 17.67

EXAMPLE 32

3-[3-Oxo-2-((2S)-pyrrolydin-2-yl)methyl-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 62.3% yield in substantially the same manner as inExample 9.

mp: 111.5-113.5° C. (50% aq. EtOH)

(KBr): 1662.3, 1633.4, 1589.1, 1529.3, 1496.5, 1467.6 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-1.90 (4H, m), 2.70-3.00 (1H, m), 3.45-3.65 (1H,m), 4.05-4.10 (2H, m), 6.90 (1H, d, J=9.6 Hz), 7.00-7.15 (2H, m),7.30-7.65 (6H, m), 8.02 (1H, d, J=8.9 Hz), 8.82 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 372 (M⁺ +1)

Anal. Calcd. for C₂₂ H₂₁ N₅ O.H₂ O C 67.85, H 5.95, N 17.98

Found: C 68.21, H 5.73, N 17.64

EXAMPLE 33

To a solution of sodium hydroxide (300 mg) in a mixture of water (20 ml)and toluene (20 ml) were added successively3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine(1.94 g), benzyltriethylammonium chloride (155 mg) and1-benzyloxycarbonylpiperidine-4-spiro-2'-oxirane (5 g), and the mixturewas refluxed for 5 hours.

The reaction mixture was cooled and extracted with chloroform (200 ml).Organic phase was separated, which was washed successively withIN-aqueous sodium hydroxide (20 ml) and saturated sodium chloride inwater, and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed onsilica gel (250 ml) eluting successively with 20% ethyl acetate inn-hexane and ethyl acetate.

Fractions containing desired product were collected and the solvent wasremoved under reduced pressure to give a crude product, which wasrecrystallized from ethanol to give3-[2-(1-benzyloxycarbonyl-4-hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(2.8 g, 79.8% yield).

mp: 175.5-177.0° C. (EtOH)

FT IR (KBr): 1697.1, 1650.8, 1583.8, 1527.3, 1490.7, 1469.5 cm⁻¹

NMR (DMSO-d₆, δ): 1.42-1.60 (4H, m), 3.00-3.30 (2H, m), 3.70-3.90 (2H,m), 4.21 (2H, s), 4.95 (1H, s), 5.06 (1H, s), 6.89 (1H, d, J=9.6 Hz),7.03-7.12 (2H, m), 7.28-7.64 (10H, m), 8.07 (1H, d, J=8.9 Hz), 8.81 (1H,d, J=6.9 Hz).

(+)-APCI/MS: 536 (M⁺ +1)

Anal. Calcd. for C₃₁ H₂₉ N₅ O₄ C 69.52, H 5.46, N 13.08

Found: C 69.32, H 5.40, N 13.01

EXAMPLE 34

A mixture of3-[2-(1-benzyloxycarbonyl-4-hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo-[1,5-a]pyridine(2.5 g), 10% palladium on carbon (500 mg, 50% wet) and concentratedhydrochloric acid (100 μl) in N,N-dimethylformamide (100 ml) was stirredunder hydrogen atmosphere.

On confirmation of the absence of the starting material by TLC check,the catalyst was removed by filtration and to the filtrate was addedtriethylamine.

The solvent was removed under reduced pressure to give a residue, whichwas chromatographed on silica gel (100 ml) eluting successively withchloroform, 9% and 20% methanol in chloroform.

Fractions containing desired product were collected and concentrated invacuo to give a crude product, which was recrystallized from ethanol togive3-[2-(4-hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(817 mg, 42.6% yield).

mp: over 260° C. (EtOH)

FT IR (KBr): 1648.8, 1581.3, 1517.7, 1490.7 cm⁻¹

NMR (DMSO-d₆, δ): 1.60-1.90 (4H, m), 2.90-3.20 (4H, m), 4.24 (2H, s),5.18 (1H, s), 6.90 (1H, d, J=9.6 Hz), 7.05-7.12 (2H, m), 7.39-7.63 (6H,m), 8.10 (1H, d, J=8.9 Hz), 8.83 (1H, d, J=6.9 Hz).

(+)-APCI/MS: 402 (M⁺ +1)

EXAMPLE 35

A mixture of3-[2-(4-hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(650 mg) and acetic anhydride (1.53 ml) in pyridine (30 ml) was stirredovernight at room temperature.

Evaporation of the solvent gave a residue, which was dissolved inchloroform (150 ml) and washed succesively with 1N aqueous hydrochloricacid, saturated sodium hydrogencarbonate in water and saturated sodiumchloride in water, and dried over magnesium sulfate.

Evaporation of the solvent gave a crude product, which wasrecrystallized from ethanol to give3-[2-(1-acetyl-4-hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine(284 mg, 39.6% yield).

mp: 163.0-165.0° C. (EtOH)

FT IR (KBr): 1646.9, 1581.3, 1527.3, 1490.7 cm⁻¹

NMR (DMSO-d₆, δ): 1.40-1.62 (4H, m), 1.97 (3H, s), 2.80-3.00 (1H, m),3.20-3.40 (1H, m), 3.50-3.70 (1H, m), 4.00-4.20 (1H, m), 4.22 (2H, m),4.93 (1H, s), 6.88 (1H, d, J=9.6 Hz), 7.05-7.10 (2H, m), 7.39-7.51 (4H,m), 7.58-7.62 (2H, m), 8.09 (1H, d, J=8.9 Hz), 8.81 (1H, d, J=6.9 Hz).

(+)-APCI/MS (m/z): 444 (M⁺ +1)

Anal. Calcd. for C₂₅ H₂₅ N₅ O₃.H₂ O C 65.06, H 5.90, N 15.17

Found: C 65.26, H 5.80, N 15.15

EXAMPLE 36

3-[2-(2-Methylthiazol-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridinewas obtained in 51.9% yield in substantially the same manner as inExample 3.

mp: 196.0-197.5° C. (EtOH)

FT IR (KBr): 1666.2, 1631.5, 1592.9, 1531.2, 1494.6, 1469.5, 1452.1,1419.4 cm⁻¹

NMR (DMSO-d₆, δ): 2.67 (3H, s), 5.38 (2H, s), 6.89 (1H, d, J=9.6 Hz),7.05 (1H, d, J=9.6 Hz), 7.05-7.10 (1H, m), 7.30-7.41 (2H, m), 7.45-7.50(3H, m), 7.59-7.65 (2H, m), 7.85 (1H, d, J=8.9 Hz), 8.80 (1H, d, J=6.9Hz).

(+)-APCI/MS (m/z): 400 (M⁺ +1)

Anal. Calcd. for C₂₂ H₁₇ N₅ OS.1/4H₂ O C 65.41, H 4.37, N 17.34

Found: 65.41, H 4.18, N 17.18

What is claimed is:
 1. A pyrazolopyridine compound of the followingformula (I): ##STR16## wherein R¹ is aryl, andR² is lower alkylsubstituted with the thiazolyl group; lower alkyl substituted withunsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2sulfur atom(s) and 1 to 3 nitrogen atom(s) which has one or moresubstituent(s); a group of the formula: ##STR17## wherein R³ is loweralkyl, ar(lower)alkyl or acyl, R⁴ is hydrogen or hydroxy, A is loweralkylene, m is an integer of 0 or 1, and n is an integer of 1 to 2; agroup of the formula: ##STR18## wherein R⁵ and R⁶ are each lower alkyl;or quinuclidinyl, or a salt thereof.
 2. A compound of claim 1, whereinR¹ is phenyl, andR² is lower alkyl substituted with thiazolyl which mayhave 1 to 3 lower alkyl substituents;a group of the formula: ##STR19##wherein R³ is lower alkyl, phenyl(lower)alkyl, lower alkanoyl, loweralkoxycarbonyl, or phenyl(lower)alkoxycarbonyl, R⁴ is hydrogen orhydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is aninteger of 1 or 2;a group of the formula: ##STR20## wherein R⁵ and R⁶are each lower alkyl; or quinuclidinyl, or a salt thereof.
 3. A compoundof claim 2, wherein R² is lower alkyl substituted with thiazolyl whichmay have 1 to 3 lower alkyl substituents, or a salt thereof.
 4. Acompound of claim 2, wherein R² is a group of the formula: ##STR21##wherein R³ is lower alkyl, phenyl(lower)alkyl, lower alkanoyl, loweralkoxycarbonyl, or phenyl(lower)alkoxycarbonyl,R⁴ is hydrogen orhydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is aninteger of 1 or 2, or a salt thereof.
 5. A compound of claim 4, whereinR² is a group of the formula: ##STR22## wherein R³ is lower alkyl,phenyl(lower)alkyl, lower alkanoyl, or lower alkoxycarbonyl,R⁴ ishydrogen, and n is an integer of 1 or 2, or a salt thereof.
 6. Acompound of claim 5, wherein R² is a group of the formula: ##STR23##wherein R³ is lower alkyl, phenyl(lower)alkyl, lower alkanoyl, or loweralkoxycarbonyl,R⁴ is hydrogen, and n is an integer of 2, or a saltthereof.
 7. A compound of claim 6, wherein R² is a group of the formula:##STR24## wherein R³ is lower alkyl,R⁴ is hydrogen, and n is an integerof 2, or a salt thereof.
 8. A compound of claim 4, wherein R² is a groupof the formula: ##STR25## wherein R³ is lower alkyl, lower alkanoyl, orphenyl(lower)alkoxycarbonyl,R⁴ is hydrogen or hydroxy, A is loweralkylene, m is an integer of 1, and n is an integer of 1 or 2, or a saltthereof.
 9. A compound of claim 8, wherein R² is a group of the formula:##STR26## wherein R³ is lower alkyl,R⁴ is hydrogen, A is lower alkylene,m is an integer of 1, and n is an integer of 1 or 2, or a salt thereof.10. A process for the preparation of the pyrazolopyridine compound ofclaim 1 or a salt thereof, which comprises,(1) reacting a compound ofthe formula (II): ##STR27## wherein R¹ is as defined in claim 8, or asalt thereof, with a compound of the formula (III);

    X--R.sup.2                                                 (III)

wherein R² is as defined in claim 8 and X is a leaving group, to give acompound of the formula (I): ##STR28## wherein R¹ and R² are each asdefined in claim 8, or a salt thereof, (2) reacting a compound of theformula (II): ##STR29## wherein R¹ is as defined in claim 8, or a saltthereof, with a compound of the formula (IV): ##STR30## wherein n is asdefined in claim 8 and R^(3a) is acyl, to give a compound of formula(Ia): ##STR31## wherein R¹ and R³ are each as defined above, or a saltthereof, (3) subjecting a compound of the formula (Ic): ##STR32##wherein R¹ is as defined above, and R^(2c) is a group of the formula:##STR33## wherein A, m, n and R⁴ are each as defined above, R^(3b) ishydrogen, or a salt thereof, to alkylation reaction, to give a compoundof the formula (Ie): ##STR34## wherein R¹ is as defined in claim 8 andR^(2e) is a group of the formula: ##STR35## wherein A, m, n, and R⁴ areeach as defined above, and R^(3c) is lower alkyl, or a group of theformula: ##STR36## wherein R⁵ and R⁶ are each as defined in claim 8, ora salt thereof, (4) subjecting a compound of the formula (Ic): ##STR37##wherein R¹ and R^(2c) are each as defined above, or a salt thereof, toacylation reaction, to give a compound of the formula (Ib): ##STR38##wherein R¹ is as defined above and R^(2b) is a group of the formula:##STR39## wherein A, m, n, R⁴ and R^(3a) are each as define above, or asalt thereof, or (5) subjecting the compound of formula (V): ##STR40##wherein R¹ and A are each as defined in claim 8, or a salt thereof, toformation reaction of thiazole ring, to give a compound of the formula(If): ##STR41## wherein R¹ and A are each as defined above, or a saltthereof.
 11. A pharmaceutical composition comprising the compound ofclaim 1 or a salt thereof in association with a pharmaceuticallyacceptable carrier or excipient.
 12. A method for treating a diseasesselected from the group consisting of depression, dementia, anxiety,pain, cerebrovascular disease, heart failure, hypertension, circulatoryinsufficiency, post-resuscitation, asystole, bradyarrhythmia,electro-mechanical dissociation, hemodynamic collapse, SIRS (systemicinflammatory response syndrome), multiple organ failure, renal failure(renal insufficiency), renal toxicity, nephrosis, nephritis, edema,obesity, bronchial asthma, gout, hyperuricemia, sudden infant deathsyndrome, immunosuppression, diabetes, ulcer, pancreatitis, Menier'ssyndrome, anemia, dialysis-induced hypotention, constipation, ischemicbowel disease, ileus, myocardial infarction, thrombosis obstruction,arteriosclerosis obliterans, thrombophlebitis, cerebral infarction,transient ischemic attack and angina pectoris, which comprisesadministering the compound of claim 1 or a salt thereof to a human beingor an animal.
 13. A process for preparing a pharmaceutical compositionwhich comprises admixing the compound of claim 1 or a salt thereof withpharmaceutically acceptable carriers or excipients.
 14. A pharmaceuticalcomposition comprising the compound of claim 1 or a salt thereof in anadenosine antagonist effective amount in association with apharmaceutically acceptable carrier or excipient.